With the advent of HAART, HIV-infected (HIV+) individuals are living longer but face health challenges such as higher rates of cardiovascular disease (CVD) and CV mortality than HIV- people. Sudden cardiac death (SCD) is a leading cause of mortality in the general population. While many HIV+ persons still die of AIDS, we discovered a much higher HIV+ SCD rate than in the general population. Our new preliminary data confirm the association of HIV with higher SCD risk in a large, independent cohort (Veterans Aging Cohort Study Virtual Cohort [VACS-VC]). Although imperfect, left ventricular systolic dysfunction (LVSD) [stable ejection fraction (EF) d35%] is the major risk assessment criterion for SCD in the HIV- population. We recently demonstrated that left ventricular systolic dysfunction (LVSD) also increases HIV+ SCD risk, with even higher risk in combination with detectable viral load (VL). Implantable cardioverter-defibrillators (ICDs) are highly effective for SCD prevention in HIV- patients with LVSD and current guidelines recommend their use for primary prevention in patients with EFd35%, but no guidelines exist for the HIV+ population. Given the competing risk of AIDS death, it is unknown whether the same EF threshold for primary prevention ICD applies and whether unique HIV+ risk factors such as QT prolonging (QTP) HAART, VL, or other factors should affect this decision. Therefore, to reduce mortality in an aging HIV+ population, it is critical to identify persons at high SCD risk. Our ultimate goal is to reduce HIV+ SCD risk and inform ICD guidelines in this population. The objective of this application is to develop a prediction model for SCD in HIV+ patients to inform guidelines for ICD implantation and determine the cardiac pathologic substrate and immunopathology of HIV+ SCDs by autopsy. We will leverage work supported by the NHLBI in two ongoing studies by extending the scope of each. First, we will calculate SCD rates and risk in HIV+ and matched uninfected controls in VACS- VC, and evaluate the relative contributions of LVSD, ECG, viral, QTP HAART and other drugs, CVD risk factors, and substance use. We also plan to develop and validate a prediction model for SCD in HIV+ patients to inform ICD guidelines, accounting for indirect effects via competing risks. Second, we address the major limitation of all prior SCD studies the lack of gold-standard autopsy data to definitively establish cause and underlying pathology by leveraging a unique, ongoing collaboration with the Medical Examiner to perform autopsy and standardized cardiac pathologic evaluation on all consecutive, incident HIV+ SCDs in San Francisco, thereby avoiding referral bias. Third, our unique access to tissue in all HIV+ SCDs will allow us an unprecedented opportunity to study both cardiac pathology and HIV viral persistence, both of which will help elucidate underlying reasons for higher observed SCD rates. These data will fundamentally advance our understanding of risk factors, mechanisms, and preventive strategies for an important cause of mortality in an aging, HIV-infected population.